Bones serve mainly as a support, and consequently bone is frequently regarded as a simple building material. However, bone is a complicated biomaterial adapted to a wide variety of requirements, stimuli and noxae to which it is exposed. Endoprostheses are available as substitutes for bones and joints. However, endoprostheses, even when biomechanically highly refined, do not have an active effect on the environmental and load factors.
A variety of disorders in humans and mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, Paget's disease, periprosthetic bone loss or osteolysis, and hypercalcemia of malignancy and metastatic bone disease. The most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women. Because osteoporosis, as well as other disorders associated with bone loss, are chronic conditions, it is believed that appropriate therapy will generally require chronic treatment.
Bisphosphonates, i.e. bisphosphonic acids or pharmaceutically acceptable salts thereof, are synthetic analogs of the naturally occurring pyrophosphate. Due to their marked affinity for solid-phase calcium phosphate, bisphosphonates bind strongly to bone mineral. Pharmacologically active bisphosphonates are well known in the art and are potent inhibitors of bone resorption and are therefore useful in the treatment and prevention of diseases involving abnormal bone resorption, especially osteoporosis, Paget's disease, hypercalcemia of malignancy, and metastatic and metabolic bone diseases.
Bisphosphonates as pharmaceutical agents are described for example in EP-A-170,228; EP-A-197,478; EP-A-22,751; EP-A-252,504; EP-A-252,505; EP-A-258,618; EP-A-350,002; EP-A-273,190; and WO-A-90/00798, each of which are incorporated herein by reference.
Pharmaceutical forms of currently marketed bisphosphonates are oral formulations (tablets or capsules) or solutions for intravenous injection or infusion. They are systemically well tolerated when administered at therapeutic doses. However, bisphosphonates as a class are irritant to skin and mucous membranes and when given orally on a continuous basis may result in digestive tract side effects, e.g., esophageal adverse events or gastrointestinal disturbances. As a consequence, and due to their low oral bioavailability, the oral route of administration has, to date, had to follow inconvenient recommendations of use for the patient.
Bisphosphonates can be classified into two groups with different modes of action. Ibandronate belongs to the more potent nitrogen-containing bisphosphonates [Russell 1999 Russell R G G, Rogers M J. Bisphosphonates: From the laboratory to the clinic and back again. Bone 25(1):97-106 (1999); Rogers M J, Gordon S, Benford H L, Coxon F P, Luckman S P, Monkkonen J, Frith J C. Cellular Molecular mechanisms of action of bisphosphonates. Cancer 88 (12) Suppl:2961-2978 (2000)]. Ibandronate is one of the most potent bisphosphonates currently under clinical development in osteoporosis and metastatic bone diseases. In animal models of bone resorption, ibandronate is 2, 10, 50 and 500 times more potent than risedronate, alendronate, pamidronate, and clodronate respectively [Mühlbauer R. C., F. Bauss, R. Schenk, M. Janner, E. Bosies, K. Strein, and H. Fleisch. B M 21.0955 a potent new bisphosphonate to inhibit bone resorption. J. Bone Miner. Res. 6: 1003-1011 (1991)].
Ibandronate inhibits bone resorption without any impairment of mineralization (Mühlbauer et al Mühlbauer R. C., F. Bauss, R. Schenk, M. Janner, E. Bosies, K. Strein, and H. Fleisch. BM 21.0955 a potent new bisphosphonate to inhibit bone resorption. J. Bone Miner. Res. 6: 1003-1011 (1991).). It has been shown to decrease osteoclastic activity, thus inhibiting bone destruction. At high doses it also reduces the number of osteoclasts (Mühlbauer et al. Mühlbauer R. C., F. Bauss, R. Schenk, M. Janner, E. Bosies, K. Strein, and H. Fleisch. BM 21.0955 a potent new bisphosphonate to inhibit bone resorption. J. Bone Miner. Res. 6: 1003-1011 (1991)).
As described, bisphosphonates are accepted as providing strong efficacy in the management of osteoporosis. However, given the administration restrictions related to low oral bioavailability and potential for gastro-intestinal effects, there is a clear opportunity for regimens which offer improved convenience and flexibility, leading to a higher level of compliance and superior patient management/satisfaction. Intermitted regimens such as, for example, once weekly administration have been described in the art.